The present invention is generally a heterocyclic spirodecane and more particularly a substituted heterocyclic spiro[4.5]decane with activity at the NK-1, substance P receptor.
The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes.
The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson""s disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases reviewed in xe2x80x9cTachykinin Receptor and Tachykinin Receptor Antagonistsxe2x80x9d, J. Auton. Pharmacol., 13, 23-93, 1993.
The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in xe2x80x9cNeuropeptides, 32(1), 1-49, (1998)xe2x80x9d and xe2x80x9cEur. J. Pharmacol., 383(3), 297-303, (1999)xe2x80x9d.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
In addition, in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.
Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
NK1 receptor antagonists have been reported to have also a beneficial effect in the therapy of traumatic brain injury (oral disclosure by Prof. Nimmo at the International Tachykinin Conference 2000 in La Grande Motte, France, Oct. 17-20, 2000 with the title xe2x80x9cNeurokinin 1 (NK-1) Receptor Antagonists Improve the Neurological Outcome Following Traumatic Brain Injuryxe2x80x9d (Authors: A. J. Nimmo, C. J. Bennett, X. Hu, I. Cernak, R. Vink).xe2x80x9d
A compound of the present invention has the formula 
wherein
R1 is hydrogen, lower alkyl, lower alkenyl, phenyl or the following groups
xe2x80x94(CH2)m-non aromatic heterocyclyl, which is unsubstituted or substituted by lower alkyl, or is
xe2x80x94(CH2)m-heteroaryl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, CF3, benzyl or cyano, or is
xe2x80x94(CH2)mxe2x80x94C(O)xe2x80x94NRRxe2x80x2,
xe2x80x94(CH2)mxe2x80x94C(O)-lower alkyl,
xe2x80x94(CH2)mxe2x80x94C(O)xe2x80x94O-lower alkyl,
xe2x80x94(CH2)mxe2x80x94O-lower alkyl,
xe2x80x94(CH2)mxe2x80x94CH[C(O)xe2x80x94O-lower alkyl]2,
xe2x80x94(CH2)mCH(OH)xe2x80x94CH2xe2x80x94O-phenyl,
xe2x80x94(CH2)mxe2x80x94CH(CF3)OH,
xe2x80x94(CH2)mxe2x80x94OH,
xe2x80x94(CH2)mxe2x80x94CN,
xe2x80x94(CH2)mxe2x80x94NRRxe2x80x2,
xe2x80x94(CH2)m-cycloalkyl or
xe2x80x94(CH2)mxe2x80x94CHF2;
R2 is hydrogen, lower alkyl, halogen or lower alkoxy;
R3 is lower alkyl, lower alkoxy, halogen or CF3;
R,Rxe2x80x2 are the same or different and are hydrogen or lower alkyl;
X is  greater than Nxe2x80x94, or  greater than CHxe2x80x94;
X1/X2 are independently from each other hydrogen, hydroxy or lower alkoxy or may be together an oxo group;
Y1/Y2 are independently from each other hydrogen, lower alkyl, xe2x80x94(CH2)m-phenyl or may be together an oxo group;
Z is a xe2x80x94(CH2)qxe2x80x94 or xe2x80x94C(O)xe2x80x94;
m is 0, 1, 2, 3 or 4;
n is 2 or 3;
nxe2x80x2 0, 1 or 2;
q is 0 or 1;
or pharmaceutically acceptable acid addition salts thereof.
A compound of formula I or its salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compound of the present invention is an antagonist of the Neurokinin 1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
Preferred compounds of the present invention include, but are not limited to:
The compound having the formula 
wherein R1, R2 and R3 are as defined above and wherein n=2 and one of R3 is F and the other of R3 is CF3.
Another preferred compound based on formula I-a has the formula I-c with R1 being hydrogen, lower alkyl, xe2x80x94(CH2)m-cycloalkyl, xe2x80x94(CH2)mxe2x80x94NRRxe2x80x2 or xe2x80x94(CH2)m-unsubstituted non-aromatic; and m=0, 1, 2, 3, 4. 
wherein R1 and R2 are as defined above; or further including R1 being hydrogen and R2 being hydrogen; and wherein R1 is phenyl or xe2x80x94(CH2)m-unsubstituted heteroaromatic alkyl. A further preferred embodiment based on structure I-c includes R1 being xe2x80x94(CH2)m-substituted heteroaryl and R2 being hydrogen; R1 being substituted or unsubstituted-(CH2)m-non aromatic heterocyclic or, xe2x80x94(CH2)mxe2x80x94NRRxe2x80x2 and R2 being hydrogen; R1 being a xe2x80x94(CH2)mxe2x80x94Oxe2x80x94O-lower alkyl, xe2x80x94(CH2)mxe2x80x94O-lower alkyl or xe2x80x94(CH2)mxe2x80x94CH(OH)xe2x80x94CH2xe2x80x94O-phenyl and R2 being hydrogen; R1 being xe2x80x94(CH2)mxe2x80x94CF3, xe2x80x94(CH2)m CN or xe2x80x94(CH2)m OH; R1 being unsubstituted or substituted-(CH2)m-heteroaryl, m is 0, 1, 2, 3 or 4; and R2 is halogen and nxe2x80x2 is 1 or 2; R1 is xe2x80x94(CH2)mxe2x80x94OH, unsubstituted or substituted-(CH2)m-heteroaryl, m is 0, 1, 2, 3 or 4; and R2 is lower alkyl or lower alkoxy; R1 is hydrogen, R2 is lower alkyl, lower alkoxy or halogen and wherein nxe2x80x2 is 1 or 2; or R1 being xe2x80x94(CH2)mxe2x80x94C(O)xe2x80x94NRRxe2x80x2, xe2x80x94(CH2)mxe2x80x94CHxe2x80x94(CF3)OH or unsubstituted or substituted-(CH2)m-non-aromatic heterocyclic wherein m is 1, 2, 3 or 4 and R2 is hydrogen or halogen.
Another preferred embodiment has the formula 
wherein R1 and R2 are as defined above. Yet another preferred embodiment based on formula I-d includes R1 being hydrogen, lower alkyl, phenyl or xe2x80x94(CH2)m-unsubstituted or substituted heterocyclic non-aromatic heterocyclic; and R2 being hydrogen or lower alkyl, m is 1, 2, 3, 4; or further includes R1 being lower alkyl, xe2x80x94(CH2)m-unsubstituted and substituted heteroaromatic, m=0, 1, 2, 3, 4; or R1 being xe2x80x94(CH2)m-unsubstituted or substituted heteroaromatic and R2 being halogen.
A further preferred embodiment includes the structure 
wherein R1 is hydrogen.
Yet another preferred embodiment has the structure 
wherein R1, R2, X1 and X2 are as defined above. A further preferred embodiment based on the structure I-f includes X1 or X2 being hydrogen, hydroxy or lower alkoxy, R1 being hydrogen, phenyl or xe2x80x94(CH2)m-unsubstituted or substituted non-aromatic heterocyclic; and R2 being hydrogen or lower alkyl.
A further preferred embodiment has the structure I-g 
wherein Y1 or Y2, R1, R2 and R3 are as above or R1 being xe2x80x94(CH2)m-substituted or unsubstituted heteroaryl. Another preferred embodiment based on the structure I-g includes R1 being hydrogen, R2 being lower alkyl and R3 being halogen, OCF3 or CF3.
A further embodiment having the formula 
wherein R1 is hydrogen, xe2x80x94(CH2)m-nonaromatic heterocyclic or lower alkyl; R2is hydrogen or halogen; Y1, Y2 and Z are as above: or wherein, Y1 and Y2 being hydrogen and Z being xe2x80x94(CH2)0xe2x80x94 or xe2x80x94C(O)xe2x80x94; or one of Y1 and Y2 being hydrogen, and the other of Y1 and Y2 being lower alkyl; Z being xe2x80x94(CH2)oxe2x80x94; and R1 being hydrogen, lower alkyl, xe2x80x94(CH2)mxe2x80x94NRRxe2x80x2, xe2x80x94(CH2)m-cyclo alkyl or xe2x80x94(CH2)m-unsubstituted non aromatic heterocyclic; or of Y1 and Y2 being hydrogen, and the other of Y1 and Y2 being lower alkyl; Z being xe2x80x94(CH2)0xe2x80x94; R1 being phenyl, xe2x80x94(CH2)mxe2x80x94O-lower alkyl, xe2x80x94(CH2)mxe2x80x94CHF2 or lower alkenyl; and R2 being lower alkyl; or further comprising one of Y1 and Y2 being hydrogen, and the other of Y1 and Y2 being lower alkyl; Z being xe2x80x94(CH2)0xe2x80x94; R1 being unsubstituted-(CH2)m-aromatic heterocyclic or substituted-(CH2)m-aromatic heterocyclic; and R2 being hydrogen or lower alkyl; or further comprising one of Y1 and Y2 being hydrogen, and the other of Y1 and Y2 being xe2x80x94(CH2)m-phenyl; Z being xe2x80x94(CH2)0xe2x80x94; R1 being hydrogen or lower alkyl; and R2 being hydrogen or lower alkyl.
A further preferred embodiment has the structure 
wherein R1 is xe2x80x94(CH2)m-cycloalkyl, xe2x80x94(CH2)m-unsubstituted heterocyclic, xe2x80x94(CH2)mxe2x80x94O-lower alkyl, xe2x80x94(CH2)mxe2x80x94NRRxe2x80x2 or xe2x80x94(CH2)mxe2x80x94C(O)-lower alkyl; and m=0, 1, 2, 3,4.
Yet another preferred embodiment has the structure 
wherein R1 is lower alkyl, X1 and X2 are as above, Y1 and Y2 are as above, R2 is hydrogen and X is  greater than CHxe2x80x94; or wherein X1 and X2 being taken together to form an oxo group, Y1 and Y2 being hydrogen, R2 being hydrogen or lower alkyl and R1 being hydrogen, lower alkyl, xe2x80x94(CH2)m-cycloalkyl, xe2x80x94(CH2)m-unsubstituted non-aromatic heterocyclic, xe2x80x94(CH2)mxe2x80x94O-lower alkyl, xe2x80x94(CH2)mxe2x80x94NRRxe2x80x2, xe2x80x94(CH2)mxe2x80x94C(O)-lower alkyl or xe2x80x94(CH2)m unsubstituted heteroaryl; or wherein X1 and X2 being taken together form an oxo group; Y1 and Y2 being taken together form an oxo group; and R1 being hydrogen, lower alkyl, xe2x80x94(CH2)m-unsubstituted non-aromatic heterocyclic or xe2x80x94(CH2)mxe2x80x94NRRxe2x80x2; and R2 being hydrogen.
A compound of the invention has the structure 
wherein
R1 is hydrogen, lower alkyl, lower alkenyl, phenyl or the following groups
xe2x80x94(CH2)m-non aromatic heterocyclic, which is unsubstituted or substituted by lower alkyl, or is
xe2x80x94(CH2)m-heteroaryl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, CF3, benzyl or cyano, or is
xe2x80x94(CH2)mxe2x80x94C(O)xe2x80x94NRRxe2x80x2,
xe2x80x94(CH2)mxe2x80x94C(O)-lower alkyl,
xe2x80x94(CH2)mxe2x80x94C(O)xe2x80x94O-lower alkyl,
xe2x80x94(CH2)mxe2x80x94O-lower alkyl,
xe2x80x94(CH2)mxe2x80x94CH[C(O)xe2x80x94O-lower alkyl]2,
xe2x80x94(CH2)mCH(OH)xe2x80x94CH2xe2x80x94O-phenyl,
xe2x80x94(CH2)mxe2x80x94CH(CF3)OH,
xe2x80x94(CH2)mxe2x80x94OH,
xe2x80x94(CH2)mxe2x80x94CN,
xe2x80x94(CH2)mxe2x80x94NRRxe2x80x2,
xe2x80x94(CH2)m-cycloalkyl or
xe2x80x94(CH2)mxe2x80x94CHF2 
R2 is hydrogen, lower alkyl, halogen or lower alkoxy;
R3 is lower alkyl, lower alkoxy, halogen or CF3;
R,Rxe2x80x2 are the same or different and are hydrogen or lower alkyl;
X1/X2 are hydrogen, hydroxy or lower alkoxy or taken together to form an oxo group;
Z xe2x80x94(CH2)qxe2x80x94 or xe2x80x94C(O)xe2x80x94;
m is 0, 1, 2, 3 or 4;
n is 2 or 3;
nxe2x80x2 0, 1 or 2;
q is 0 or 1;
or pharmaceutically acceptable acid addition salts thereof.
A preferred embodiment of the compound with structure I-k has the structure 
wherein is R1 as above or wherein R1 being hydrogen, lower alkyl, xe2x80x94(CH2)m-cycloalkyl, xe2x80x94(CH2)mxe2x80x94NRRxe2x80x2 or xe2x80x94(CH2)m-unsubstituted non-aromatic; and m=0, 1, 2, 3, 4.
Objects of the present invention are the compounds of formula I and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.
The compounds of formula I can also be used in form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add to the value of the present compounds advantages in absorption, pharmocokinetics in distribution and transport to the brain.
The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a saturated straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
Preferred lower alkyl groups are groups with 1-4 carbon atoms.
As used herein, the term xe2x80x9clower alkenylxe2x80x9d denotes a unsaturated straight- or branched-chain alkyl group containing from 2-7 carbon atoms, for example, ethenyl, propenyl, isopropenyl, n-butenyl, i-butenyl, t-butenyl and the like.
Preferred lower alkyl groups are groups with 2-4 carbon atoms.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated carbocyclic group, containing 3-6 carbon atoms.
The term xe2x80x9cnon aromatic heterocyclylxe2x80x9d denotes, for example, pyrrolidinyl, 5-oxo-pyrrolidinyl, 2-oxa-oxazolidinyl, piperidyl, piperazinyl, morpholinyl, imidazolidinyl or pyrazolidinyl. Preferred groups are pyrrolidinyl, 5-oxo-pyrrolidinyl, 2-oxa-oxazolidinyl, piperidyl, piperazinyl or morpholinyl.
The term xe2x80x9cheteroarylxe2x80x9d denotes, for example pyridinyl, 1,3,5-triazinyl, pyrimidinyl, quinoxalinyl, pyrazinyl, isoxazolyl, benzoimidazolyl, 1,2,4-oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, piperazinyl or piperidyl. Preferred groups are pyridinyl, 1,3,5-triazinyl, pyrimidinyl, quinoxalinyl, pyrazinyl, imidazolyl, thiazolyl, isoxazolyl, benzoimidazolyl, 1,2,4-oxadiazolyl, furyl and thienyl.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
Preferred are all compounds, wherein R3 is trifluoromethyl and n is 2.
Exemplary preferred are compounds, in which X is  greater than Nxe2x80x94, X1/X2 are together an oxo group and Y1/Y2 are both hydrogen, for example the following compounds:ps
8-(3,5-Bis-trifluoromethyl-benzoyl)-3-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one,
8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-3-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-1,3,8-triaza-spiro[4.5]decan-4-one,
8-(3,5-,bis-trifluoromethyl-benzoyl)-3-pyridin-3-yl-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one,
8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-isopropylamino-ethyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one,
8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-pyrrolidin-1-yl-ethyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one,
8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-3-pyridin-4-yl-1,3,8-triaza-spiro[4.5]decan-4-one,
8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-3-methyl-1,3,8-triaza-spiro[4.5]decan-4-one,
8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-3-(3-dimethylamino-propyl)-1,3,8-triaza-spiro[4.5]decan-4-one,
8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-3-pyridin-4-yl-1,3,8-triaza-spiro[4.5]decan-4-one and
8-(3,5-bis-trifluoromethyl-benzoyl)-3-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one.
Further preferred are compounds, in which X is  greater than Nxe2x80x94, X1/X2 are together an oxo group and one of Y1/Y2 is hydrogen and the other is different from hydrogen.
Examples of such compounds are:
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-2-benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-phenyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-3-pyridin-3-yl-methyl-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2,3-dimethyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2methyl-1-phenyl-3-(2-pyrrolidin-1-yl-ethyl)-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-dimethylamino-propyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2,3-dimethyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-3-(2-piperazin-1-yl-ethyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-3-(2-pyrrolidin-1-yl-ethyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-3-(2-piperidin-1-yl-ethyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-methoxy-ethyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one,
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-3-(2-morpholin-4-yl-ethyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and
(rac)-8-(3,5-dichloro-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one.
Preferred are further compounds, wherein X is  greater than Nxe2x80x94, X1/X2 and Y1/Y2 are oxo groups, for example the following compounds:
8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione,
8-(3,5-bis-trifluoromethyl-benzoyl)-3-pyridin-3-yl-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione,
3-(1H-benzoimidazol-2-yl-methyl)-8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione,
8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-methyl-thiazol-4-yl-methyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione,
8-(3,5-bis-trifluoromethyl-benzoyl)-3-furan-2-yl-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione,
8-(3,5-bis-trifluoromethyl-benzoyl)-3-furan-2-yl-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and
8-(3,5-bis-trifluoromethyl-benzoyl)-3-thiophen-2-yl-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione.
Preferred are further compounds, wherein X is  greater than C=, for example the following compounds:
8-(3,5-bis-trifluoromethyl-benzoyl)-2-(2-pyrrolidin-1-yl-ethyl)-4-o-tolyl-2,8-diaza-spiro[4.5]dec-3-en-1-one and
8-(3,5-bis-trifluoromethyl-benzoyl)-2-(3-dimethylamino-propyl)-4-o-tolyl-2,8-diaza-spiro[4.5]dec-3-en-1-one.
Further preferred are compounds, wherein X is  greater than CHxe2x80x94, for example the following compound:
(rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro[4.5]decan-1-one.
The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
reacting a compound of formula 
xe2x80x83with a compound of formula 
xe2x80x83to a compound of formula 
xe2x80x83wherein L is a leaving group, for example halogen, such as chlorine, and the other substituents have the significances given above, or
reacting a compound of formula 
xe2x80x83with a compound of formula
xe2x80x83in the presence of sodium hydride or in the presence of potassium carbonate and CuCl, wherein in formula IV L is a leaving group, for example chlorine,
to give a compound of formula 
xe2x80x83wherein the other substituents have the significances given above with the proviso that R1 is not xe2x80x94(CH2)mxe2x80x94OH and X1/X2 are not hydroxy, or
reacting a compound of formula 
xe2x80x83with a compound of formula 
xe2x80x83to a compound of formula 
xe2x80x83wherein TBDMS is a tert-butyldimethylsilyl group and the further definitions of substituents is given above, or
reacting a compound of formula 
xe2x80x83after activation as mesylate with a corresponding amine of formula
RRxe2x80x2NH
xe2x80x83to give a compound of formula 
xe2x80x83wherein the definitions of substituents are given above, or
reacting a compound of formula 
xe2x80x83with a compound of formula 
xe2x80x83to a compound of formula 
xe2x80x83wherein R4 is lower alkyl and the definitions of the other substituents are given above, or
reacting a compound of formula 
xe2x80x83with a compound of formula 
xe2x80x83to a compound of formula 
xe2x80x83wherein R1 is phenyl or heteroaryl, optionally substituted as described above and the definition of the remaining substituents is given above, or
cyclizing a compound of formula 
xe2x80x83to a compound of formula 
xe2x80x83wherein the substituents are described above, or
reacting a compound of formula 
xe2x80x83with 
xe2x80x83to give a compound of formula 
xe2x80x83wherein the substituents are described above, or
treating a compound of formula 
xe2x80x83with hydrogen on Pd/C and then with (CF3)2C6H3COCl to obtain a compound of formula 
xe2x80x83wherein the substituents are given above, or
modifying one or more substituents R1-R3 within the definitions given above, and if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.
The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts.
The following schemes 1-17 describe the processes for preparation of compounds of formula I in more detail. The starting materials are known compounds and may be prepared according to methods known in the art.
In the schemes the following abbreviations have been used:

wherein in scheme 1 L is a leaving group, for example halogen, such as chlorine, and the other substituents have the significances given above.
A solution of a compound of formula II, for example 3,5-bis(trifluoromethyl)benzoyl chloride in dichloromethane, is added to a mixture of a compound of formula III, which is for example 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and triethylamine in dichloromethane. The reaction is carried out at room temperature.
Compounds of examples 1 to 3 have been prepared according to scheme 1. 
The definition of substituents is described above.
This reaction is carried out in the presence of sodium hydride and/or NMP (N-methyl-2-pyrrolidone)/1,2-dimethoxyethane. To this suspension is added a compound of formula I-1 and then a compound of formula IV is added, which is, for example, 4-(2-chloroethyl)morpholine, 3-(chloromethyl)pyridine, 2-chloro-4,6-dimethoxy-1,3,5-triazine, 1-(2-chloroethyl)piperidine, 1-(2-chloroethyl)pyrrolidine, 2-bromoacetamide, 2-chloro-N,N-dimethylacetamide, methyl bromoacetate, bromomethyl methylether, dimethyl bromomalonate, phenylglycidylether, 2,4,6-trichloropyrimidine, 2-chloro-5-(trifluoromethyl)pyridine, 3-bromo-1,1,1-trifluoro-2-propanole, 2-picolylchloride, 4-chloromethylpyridine, 2,4-dichloropyrimidine, methyliodide, 1-benzyl-(2-chloromethyl)-imidazole, 5-chloromethyl-2-oxazolidinone, 1-chloro-2-dimethylaminoethane, 1-(2-chloroethyl)pyrrolidine, 4-chloromethyl-2-methylthiazole, 4,6-dichloropyridine, 2,3,5-trichloropyridine, 2-chloro-4-(trifluoromethyl)-pyrimidine, 2-chloro-pyridine, 2-chloro-N,N-dimethylacetamide, 3-dimethylaminopropylchloride, 4-(chloromethyl)3,5-dimethylisoxazole or 2,4-dichloro-6-methylpyrimidine.
Examples 4 to 21, 25 to 47, 70 to 82 and 86, 87 and 134 have been described in accordance with scheme 2 in more detail. 
The definition of substituents is described above.
This reaction is carried out under conditions described in scheme 2, with a compound of formula I-1 and of formula V, which compound is, for example (3-bromopropoxy)-tert.-butyldimethylsilane. In a solution of HCl and ethanol the intermediate TBDMS-ether is cleaved.
Examples 22 to 24 have been described in accordance with scheme 3. 
The definition of substituents is given above.
A solution of a compound of formula I-2 and triethylamine in dichloromethane is added to a cooled solution of methanesulfonyl chloride in dichloromethane or DMF and then sodium bicarbonate and an amine of the formula RRxe2x80x2NH is added to obtain a compound of formula I-3.
Examples 48 to 58 have been described in accordance with scheme 4. 
In scheme 5 R4 is lower alkyl and the definition of the other substituents is given above.
In accordance with this scheme to a mixture of a compound of formula I-1, cesium fluoride and tetraethoxysilane, a compound of formula VI, for example ethyl acrylate, is added. The reaction is carried out at room temperature.
Examples 59 and 60 have been prepared as described in scheme 5. 
The definition of substituents is described above.
This reaction is carried out with a mixture of a compound of formula I-1 in the presence of potassium carbonate, CuCl and tris[2-(2-methoxyethoxy)-ethyl]-amine, and with a solution of a compound of formula IV, which is, for example, 4,6-dichloropyrimidine in xylene.
Example 61 has been described in accordance with scheme 6. 
The definition of substituents is given above.
A mixture of a compound of formula I-1, a boronic acid of formula VII, cupric acetate and triethylamine in dichloromethane is stirred at room temperature. Chromatography on silica gel yielded the desired compound of formula I.
Examples 62, 83 and 84 describe the process of scheme 7 in more detail. 
The definition of substituents is described above.
A mixture of a compound of formula VIII, formic acid and acetic anhydride is stirred at room temperature to give the intermediate N-formyl derivative, which is treated with formic acid and acetic acid to give the intermediate amide. The amide is dissolved in triethyl orthoformate and boiled. After evaporation the solid is dissolved in methanol and sodium borohydride at room temperature is added. The desired product is obtained by chromatography on silica gel.
Examples 63 to 68 and 85 describe the processes in accordance with scheme 8 in more detail. 
The definition of substituents is described above.
An ethylenediamine-trimethylaluminium complex is added to a solution of a compound of formula I-6 in toluene. The reaction is carried out at about 120xc2x0.
Examples 69 has been described in accordance with scheme 9. 
The definition of substituents is described above.
A solution of a compound of formula IX in dichloromethane is added with cooling to a solution of 4-piperidone trifluoroacetate and triethylamine. The reaction is carried out at room temperature.
Example A describes this process in more detail. 
The definition of substituents is described above.
To a solution of a compound of formula XI in acetic acid is added with cooling a compound of formula XII, for example 3-chloroaniline, and TMSCN.
Examples B, C, D, E, F, G and H are prepared in accordance with scheme 11. 
The definition of substituents is described above.
In accordance with scheme 12 to a solution of 1-benzyl-piperidin-4-one (XI-1) in acetic acid is added a compound of the formula (R2)nxe2x80x2xe2x80x94C6H4xe2x80x94Zxe2x80x94NH2, for example aniline, and TMSCN. To a solution of the intermediate amino nitrile in formic acid is added with cooling acetic anhydride and the obtained foam is dissolved in formic acid and acetic acid. The intermediate is cyclized by boiling in triethylorthoformate and subsequently treated with a Grignard reagent, for example with methylmagnesium bromide. The intermediate is treated with hydrogen and palladium on charcoal in methanol. The last step is the treatment of the obtained solution with 3,5-bis-trifluoromethyl benzoylchloride to obtain a compound of formula I-8.
Examples 91 to 109, 112, 114 to 120 and 132 describe the processes in accordance with scheme 12 in more detail. 
The definition of substituents is described above.
To a solution of the compound of formula XI-1 in acetic acid a compound of formula (R2)nxe2x80x2xe2x80x94C6H4xe2x80x94Zxe2x80x94NH2, for example aniline, and TMSCN are added. Then, to a solution of the intermediate amino nitrile, chlorosulfonyl isocyanate is added. The solid is suspended in hydrochloric acid and refluxed. The intermediate is treated with hydrogen and palladium on charcoal. The last step is the treatment with (CF3)2C6H3COCl to give a compound of formula I-9.
Examples 110, 111 and 113 are described in more detail in accordance with scheme 13. 
The definition of substituents is described above.
To a solution of 1-benzyl-piperidin-4-one (XI-1) in acetic acid is added a compound of formula (R2)nxe2x80x2xe2x80x94C6H4xe2x80x94Zxe2x80x94NH2, for example aniline, and TMSCN. To a solution of the obtained intermediate amino nitrile in dichloromethane is added chlorosulfonyl isocyanate. The obtained white solid is suspended in HCl and refluxed. The reduction is then performed with diisobutyl aluminium hydride. The intermediate n-benzyl protected spiropiperidine is treated with hydrogen and palladium on charcoal. After stirring in a hydrogen atmosphere at room temperature (CF3)2C6H3COCl is added to give a compound of formula I-10.
Examples 129 and 130 are described in accordance with scheme 14. 
The definition of substituents is described above.
To a solution of 1-benzyl-piperidin-4-one (XI-1) in acetic acid is added a compound of formula (R2)nxe2x80x2xe2x80x94C6H4xe2x80x94Zxe2x80x94NH2, for example o-toluidine, and TMSCN. The solution of the obtained intermediate amino nitrile is dissolved in acetic acid PtO2, and the reaction mixture is hydrogenated at room temperature. To the solution of the obtained intermediate in dichloromethane and triethylamine is added trichloromethyl chloroformat at about xe2x88x9220xc2x0 C. The obtained intermediate N-benzyl protected spiropiperidine is treated with hydrogen and palladium on charcoal. After stirring in a hydrogen atmosphere at room temperature (CF3)2C6H3COCl is added to give a compound of formula I-11.
Example 131 is prepared in accordance with scheme 15. 
To a solution sodium ethoxide is added benzyl cyanide and N-benzyl-4-piperidone (XI-1) and the reaction is run at 85xc2x0 C. for 3 h. Workup with concentrated hydrochloric gives the intermediate (1-benzyl-piperidin-4-ylidene)-phenyl-acetonitrile which is treated with potassium cyanide. The obtained intermediate N-benzyl protected spiropiperidine is treated with hydrogen and palladium on charcoal. After stirring in a hydrogen atmosphere at room temperature (CF3)2C6H3COCl is added to give a compound of formula I-12.
Example 156 is prepared in accordance with scheme 16. 
The definition of substituents is described above.
To a solution sodium ethoxide is added benzyl cyanide and N-benzyl-4-piperidone (XI-1) and the reaction is run at 85xc2x0 C. for 3 h. Workup with concentrated hydrochloric gives the intermediate (1-benzyl-piperidin-4-yl-idene)-phenyl-acetonitrile which is treated with potassium cyanide. Reduction of one carbonyl group is performed with an excess of diisobutylaluminium hydride and elimination is performed with acetic acid. The obtained intermediate N-benzyl protected spiropiperidine is treated with hydrogen and palladium on charcoal. After stirring in a hydrogen atmosphere at room temperature (CF3)2C6H3COCl is added to give a compound of formula I-13.
Example 161 is prepared in accordance with scheme 17.
As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that all of the compounds of formula I of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
The compounds were investigated in accordance with the tests given hereinafter.
The affinity of test compounds for the NK1 receptor was evaluated at human NK1 receptors in CHO cells infected with the human NK1 receptor (using the Semliki virus expression system) and radiolabelled with [3H]substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%) leupeptin (8 xcexcg/ml), MnCl2 (3 mM) and phosphoramidon (2 xcexcM). Binding assays consisted of 250 xcexcl of membrane suspension (1.25xc3x97105 cells/assay tube), 0.125 xcexcl of buffer of displacing agent and 125 xcexcl of [3H]substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2xc3x972 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
The affinity to the NK-1 receptor, given as pKi, is in the range of 6.5-8.8 for all of the exemplified compounds of the present invention. Particular examples of such compounds are
The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xaes, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragxc3xa9es and hard gelatine capsules.
Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of formula I should be appropriate, although the above upper limit can also be exceeded when necessary.